The present invention relates to novel therapeutically active compounds and more particularly, to novel serotonin reuptake inhibitors (SRI) and their use as therapeutic agents for treating platelet-aggregation associated diseases and disorders, as well as other peripheral medical conditions.
Acute myocardial infarction (AMI or MI), also known as a heart attack, is a disorder that occurs when the blood supply to a part of the heart is interrupted, and the resulting ischemia (shortage in oxygen) causes damage and potential death of heart tissue. Currently MI is the leading cause of death for both men and women all over the world, causing 12.6% of deaths worldwide (a higher mortality rate than cancer). According to the World Health Organization reports, rates of MI-related death are much higher in countries with higher life expectancies, and keep increasing as better treatments become available for common cancers such as colon and breast cancers. Some of the main risk factors are a previous history of vascular disease such as atherosclerotic coronary heart disease and/or angina, a previous heart attack or stroke, any previous episode of abnormal heart rhythms or syncope, age (men over 40 and women over 50), smoking, excessive alcohol consumption, the abuse of certain illicit drugs, high triglyceride levels, high LDL and low HDL, diabetes, high blood pressure, obesity, and chronically high levels of mental stress.
The risk of a new or recurrent myocardial infarction decreases with strict blood pressure management and lifestyle changes, primarily smoking cessation, regular exercise, a sensible diet for patients with heart disease, and limitation of alcohol intake. Patients whom experienced a coronary event are typically prescribed several chronic medications with the aim of preventing secondary cardiovascular events such as further myocardial infarctions, congestive heart failure or cerebrovascular accident (CVA). Such medications include anti-platelet drugs such as aspirin and/or clopidogrel (Plavix) which reduce the risk of plaque rupture and recurrent myocardial infarction.
Ischemic heart disease or coronary artery disease (CAD), stroke, or pulmonary embolism, are all diseases that share the phenomena of spontaneous formation of small blood clots, unrelated to injury of blood vessels and initiated by aggregation of blood platelets inside intact blood vessels. These small platelet aggregates are carried in the blood stream until they reach small capillaries, where they might cause local ischemia by blocking small capillaries in the heart, lungs or brain tissues. Such tiny clots are also implicated in the blockade of blood vessels in the legs, a common complication of diabetes. Hence, drugs that can treat ischemia can be used beneficially to treat medical conditions which include ischemic heart disease (IHD), myocardial infarction (MI), cerebral stroke, pulmonary embolism, and type-2 diabetes-associated vascular abnormalities.
Aspirin, introduced in the late 19th century by Bayer (Germany), is the first synthetic drug ever marketed as a pain-relief and anti-inflammatory drug. In the second half of the 20th century aspirin has been shown to act by inhibiting the activity of cyclooxygenase enzymes, a key step in the synthesis of prostaglandins, endogenous mediators of pain and inflammation. It was realized that since prostaglandins play a key role in the increased platelet aggregation associated with inflammation, aspirin can act as a potent anti-platelet agent when given chronically, and therefore can protect from diseases such as CAD, MI, stroke and pulmonary embolism. Thus, aspirin has become the most widely prescribed drug globally, and is given as preventive treatment in CAD [1, 2]. Aspirin is also prescribed as preventive treatment against cardiovascular complications in type-2 diabetes [3].
However, blocking prostaglandins production by aspirin cannot fully protect individuals from increased platelet aggregation, mainly since it has been found that additional endogenous modulators (such as, for example, thrombin and adenosine) are implicated in platelet aggregation during inflammation. Moreover, aspirin is contra-indicated in individuals with ulcers, gastritis, ulcerative colitis, due to its tendency to increase gastrointestinal bleeding. Therefore, there is clinical validity to develop additional anti-platelet drugs, as add-on therapy for individuals who receive chronic aspirin, or as replacement for aspirin in individuals in whom aspirin is contra-indicated.
Clopidogrel causes irreversible inhibition of the adenosine diphosphate (ADP) receptor (P2Y12) on platelet cell membranes, which is a key participant in the process of platelet aggregation. The obturation of this receptor inhibits platelet aggregation by blocking activation of the glycoprotein IIb/IIIa pathway. Clopidogrel is indicated for prophylactic prevention of vascular ischaemic events in patients with symptomatic atherosclerosis, in cases of acute coronary syndrome without ST-segment (the part of an electrocardiogram immediately following the QRS complex and merging into the T wave) elevation (NSTEMI) along with aspirin, and for the prevention of thromboembolism after placement of intracoronary stent also along with aspirin. The use of clopidogrel over aspirin is recommended for patients with a history of gastric ulceration requiring anti-platelet therapy. However, a recent study has shown that patients with healed aspirin-induced ulcers receiving aspirin plus the proton pump inhibitor esomeprazole had a lower incidence of recurrent ulcer bleeding than patients receiving clopidogrel. Additionally, antithrombotic doses of clopidogrel were found to have limited effects on bleeding and standard measures of platelet aggregation [4]. Furthermore, clopidogrel is associated with other serious adverse effects which include severe neutropenia, thrombotic thrombocytopenic purpura, hemorrhage which is aggravated by the co-administration of aspirin, gastrointestinal hemorrhage, cerebral hemorrhage and erectile dysfunction.
Serotonin (5-HT) is a major central nervous system (CNS) monoamine neurotransmitter, which is synthesized in serotonergic neurons in the CNS (about 10%) and enterochromaffin (EC) cells (Kulchitsky cells) in the gastrointestinal tract of animals (about 90%). Serotonin is also found in many mushrooms and plants. Serotonin is stored outside the brain mostly in platelets of the blood stream. Serotonin was first isolated and named in 1948 by Rapport, Green and Page, who identified it initially as a vasoconstrictor substance in blood serum—hence serotonin, a serum agent affecting vascular tone. Rapport and co-workers also identified serotonin chemically as 5-hydroxytryptamine (5-HT), and since then it was studied and found to exhibit a wide range of physiological roles.
Most of 5-HT is synthesized by tryptophan hydroxylase-1 (TPH1), which is expressed almost exclusively in the enterochromaffin cells of the gastrointestinal tract. 5-HT is secreted into the blood and taken up by the 5-HT transporter (5-HTT) primarily into platelets, which are the richest reservoir of 5-HT in the periphery. In the blood, 5-HT is stored almost exclusively in the dense granules of platelets and is almost absent in the plasma. Notably, blood lymphocytes (both B and T lymphocytes) also express functional 5-HTT and can accumulate 5-HT. However, the capacity of lymphocytes to store and to release 5-HT has not been proven to date; the lymphocyte reservoir is apparently smaller compared with the large platelets 5-HT storage capacity.
As a CNS active substance, serotonin plays an important role in the regulation of aggression, mood, body temperature, sleep, vomiting, sexual drive and appetite. Low levels thereof or low bioavailability are associated with several disorders such as increased aggressive and angry behaviors, clinical depression, obsessive-compulsive disorder (OCD), migraine, irritable bowel syndrome (IBS), tinnitus, fibromyalgia (FM or FMS), bipolar disorder, anxiety disorders and intense religious experiences. In addition, abnormal serotonergic neurons have been associated with the risk of sudden infant death syndrome (SIDS). When taken orally, 5-HT does not pass into the serotonergic pathways of the CNS because it cannot cross the blood-brain barrier (BBB).
In addition to its CNS activities, 5-HT is involved in several peripheral activities; these include cardiovascular modulating effects (both vasoconstrictor and vasodilator), potent pro-thrombotic activity, endothelial mitogenic action, as well as immune modulating effects.
One method for modulating peripheral 5-HT levels is the chronic use of serotonin-selective reuptake inhibitor drugs (SSRIs) such as alaproclate, dapoxetine, etoperidone, citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline and zimelidine. Of note however, all the above-mentioned are known to penetrate the BBB readily and thus have CNS activities in addition to their peripheral activities on modulating 5-HT levels. Indeed the SSRIs are routinely used for treating CNS conditions such as clinical depression, obsessive-compulsive disorder, and additional mood disorders and are hence known to belong to the class of antidepressant drugs.
Stemming from the vast research on serotonin it transpired that blocking the 5-HT transporter (5-HTT) activity in the periphery by SSRI drugs leads to decreased platelet 5-HT storage capacity, and thereby leads to reduced biological availability of platelet 5-HT. This in turn leads to reduced platelet aggregation during inflammation.
Several studies, including use of transgenic mice deficient in peripheral 5-HT synthesis, have suggested that reducing peripheral 5-HT levels may be beneficial for coronary artery disease (CAD) patients. In other words, reducing platelets 5-HT storage capacity is reflected in anti-thrombotic consequences. Indeed, epidemiological studies have indicated that patients who are treated chronically with SSRI drugs are less likely to suffer from MI and CAD [5-8].
Among the lines of evidence pointing towards potential beneficial effects of reduced peripheral 5-HT, is the observation that transgenic mice deficient in TPH1 (tphl −/−) and therefore in 5-HT synthesis exhibit reduced thrombosis risk [9].
There are several clinical studies showing that patients who take SSRI drugs chronically are less likely to develop thrombosis-related disorders, most notably, MI, stroke and CAD [7, 8, 10]. A randomized study compared sertraline (marketed under the name Zoloft as well as many other trade names) versus placebo in depressed post-acute coronary syndromes (ACS) patients, administered in addition to the standard anti-platelet agents aspirin and clopidogrel [10]. In this study, plasma markers of platelet activation were monitored, and the results showed that sertraline treatment was associated with substantially attenuated release of platelet/endothelial biomarkers as compared to the placebo treatment.
Furthermore, a multi-center study that included 68 hospitals, which focused on the effects of SSRI treatment on first time myocardial infarction (MI), indicated a protective effect: the odds ratio for MI among current SSRI users compared with nonusers was 0.35 [7].
The largest study to date compared 1080 myocardial infarction (MI) cases and 4256 controls during a 3-year period [8]. Unlike the former studies, this study included patients receiving various SSRIs (paroxetine, fluoxetine, or sertraline) as well as non-SSRI antidepressants and tricyclic antidepressants. The study reported that overall, SSRI use was associated with a large reduction of MI risk (odds ratio of 0.59; meaning, a 41% reduction of MI risk during the 3-year follow-up period); such reductions were not observed for the non-SSRI antidepressants. Notably, the two anti-platelet agents in current clinical use, aspirin and clopidogrel, were reported to reduce MI risk by only 20% and 10% respectively [1].
It should be noted that the prospective beneficial effects of SSRIs for reducing MI, CAD and ischemic risk are not necessarily limited to their direct capacity for reducing thrombosis. An additional and attractive mechanism of action for the observed clinical benefits in chronic heart failure (CHF) patients might reflect reduced endothelial mitogenesis following platelet-endothelial adhesion, and hence, reduced restenosis at the coronary arteries [11]. Coronary restenosis occurs as a result of exaggerated coronary endothelial mitogenesis, which might involve increased activation of endothelial cells by adhering platelets and serotonin released by the latter. It is further established that serotonin is mitogenic for endothelial cells.
Over the years, additional potential clinical indications for probable beneficial effects of SSRI or other serotonin-modulating compounds for non-psychiatric indications have been unveiled. These include chronic disorders for which increased platelet activity has been reported and implicated in the disease progression. This diseases and disorders include pulmonary hypertension, in which a 50% reduction in the risk of death was noted in SSRI users [12]; restenosis, following elective coronary stenting of native coronary arteries which was shown to be reduced by blocking the action of peripheral 5-HT [13]; rheumatoid arthritis [14], diabetes, where the SSRI drug fluvoxamine was shown to improve hepatic glucose uptake in a dog [15], autoimmune disorders (e.g., multiple sclerosis, psoriasis), where mice lacking the 5-HTT (a situation mimicking chronically blocking the 5-HTT with an SSRI drug) were shown to be less sensitive to induction of experimental autoimmune encephalomyelitis (EAE), a well-defined animal model of autoimmune disease of the central nervous system mimicking features of the human disease multiple sclerosis [16], kidney failure [17] and inflammatory bowel disease (IBD) [18].
In recent publications, a potential therapeutic application of 5-HTT inhibitors in human pulmonary arterial hypertension have also been suggested, where it was shown that transgenic mice over-expressing 5-HTT in smooth muscle develop pulmonary hypertension, indicating that blocking the 5-HTT with SSRI could be protective against this disorder [19].
However, currently, chronic treatment with SSRI drugs is reserved in the clinic for affective disorders (also known as mood disorders), most notably, depression and compulsive disorders, and is unwarranted as chronic treatment for people at risk of CAD, MI, stroke or other ischemic diseases, which forms a large segment of the population over the age of 50 years. This is mainly due to the severe adverse CNS-related side-effects of chronic SSRI treatment, such as nausea, drowsiness or somnolence, headache, clenching of teeth, extremely vivid and strange dreams, dizziness, changes in appetite, weight loss/gain, changes in sexual behavior (reduced libido), increased feelings of depression and anxiety which may sometimes provoke panic attacks, tremors, autonomic dysfunction including orthostatic hypotension, thoughts of suicide, depersonalization (derealization), flattened emotions and increased aggressiveness. Out of this list of known adverse effects, the three most frequently observed in SSRI users are decreased libido, flattened emotions and increased aggressiveness.
There is thus a widely recognized need for novel compounds, which would exhibit a serotonin reuptake inhibitory activity mainly in the periphery, and hence could be utilized in the treatment of various peripheral disorders, without entering the CNS and affecting brain 5-HT storage and actions in the brain.